We have recently found that compounds corresponding to substituted oxazole derivatives (WO2005040139) are potent and selective of certain tyrosine kinase inhibitors and more particularly of c-kit, bcr-abl, Flt-3 and mutant forms thereof. These compounds are good candidates for treating diseases such as autoimmunes diseases, inflammatory diseases, cancers and mastocytosis. In view of the growing interest of such compounds as candidate medicament, a process allowing high scale production is needed.
Several publications have described the synthesis of functionalized 2-aminoaryloxazole compounds. Examples include, Turchi, I. J. (Ed. Heterocyclic Compounds, J. Wiley and sons: N.Y., 1986); U.S. Patent US 2002/0143176A1 as well as publications by Froyen P. (Phosphorus, Sulfur and Silicon, 1991, vol 60 pp. 81-84) and Murali Dhar, T. G., et al. (Bioorganic § Medicinal Chemistry Letters, 2002, vol 12, pp. 3125-3128). However, and as summarized below, conventional methodologies have synthetic disadvantages concerning one or more of these characteristics: yield, scalability to multi-gram synthesis, highly reactive by-product formation, hazardous reaction conditions, impurity formation, number of synthetic steps, reaction conditions, and purifications. For example, the synthesis of 2-aminoaryloxazole 5 via Iminophosphorane 4 (Scheme 1) present two major disadvantages: a risk of explosions due to the presence of azide 3 (Murali Dhar, T. G., et al. (Organic Letters, 2002, vol 4 (12), pp. 2091-2093)), and rapid decomposition under reaction conditions of 2-Azido Ketone 3, when 5-aromatic moiety is highly functionalized. This decomposition adversely affects product recovery, and the reaction is characterized by numbers of byproducts and a yield that is too low to allow for its implementation in a scale-up process.

In contrast with conventional methodologies, the present invention provides a synthetic method that is characterized by at least one of the following features: good yields, with embodiments producing at least about 70% yield of the functionalized 2-aminooxazole derivative of interest; regioselectivity; purification by simple procedures, such as crystallization; and suitability for the production of multi-gram quantities of the products of interest. A series of 2-aminooxazole derivatives are described herein. Also described are methods for preparing these derivatives, that are amenable to large-scale procedures.
The process according to the present invention presents the advantages of obtaining 5-functionalised oxazole in good yield such 5-carboxyl-oxazole or 5-cyano-oxazole.